Synthesis of high functionality and quality mannose-grafted lipids to produce macrophage-targeted liposomes

The mannose receptor, which is responsible for tumor invasion, proliferation, and metastasis in the tumor microenvironment, is overexpressed in tumor-associated macrophages. Mannose is commonly applied to PEGylated liposomes in macrophage-targeted cancer therapy. To develop a high functionality and quality (HFQ) lipid for macrophage-targeted liposomes, we designed a novel mannosylated lipid with improved mannose receptor binding affinity using serine-glycine repeats (SG)_n. We synthesized Man(S)-(SG)₅-SSK-K(Pal)₂ using only a fluorenylmethyloxycarbonyl (Fmoc) protecting group solid-phase peptide synthesis method, which produced a high-quality lipid at a moderately good yield. We then prepared Man-(SG)₅/PEGylated liposomes using a post-insertion technique to insert Man(S)-(SG)₅-SSK-K(Pal)₂ into the PEGylated liposomes. In vitro cell investigations revealed that the Man-(SG)₅/PEGylated liposomes effectively associated with mouse peritoneal macrophages by interacting with the mannose receptors. The results suggest that we produced a novel high-quality, highly functional mannosylated lipid that is suitable for clinical drug delivery applications.